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Artificial intelligence (AI) methods promise to aid this task by learning patterns of disease progression from large corpora of health records\n                    <jats:sup>4,5<\/jats:sup>\n                    . However, their potential has not been fully investigated at scale. Here we modify the GPT\n                    <jats:sup>6<\/jats:sup>\n                    (generative pretrained transformer) architecture to model the progression and competing nature of human diseases. We train this model, Delphi-2M, on data from 0.4\u2009million UK Biobank participants and validate it using external data from 1.9\u2009million Danish individuals with no change in parameters. Delphi-2M predicts the rates of more than 1,000 diseases, conditional on each individual\u2019s past disease history, with accuracy comparable to that of\u00a0existing single-disease models. Delphi-2M\u2019s generative nature also enables sampling of synthetic future health trajectories, providing meaningful estimates of potential disease burden for up to 20 years, and enabling the training of AI models that have never seen actual data. Explainable AI methods\n                    <jats:sup>7<\/jats:sup>\n                    provide insights into Delphi-2M\u2019s predictions, revealing clusters of co-morbidities within and across disease chapters and their time-dependent consequences on future health, but also highlight biases learnt from training data. In summary, transformer-based models appear to be well suited for predictive and generative health-related tasks, are applicable to population-scale datasets and provide insights into temporal dependencies between disease events, potentially improving the understanding of personalized health risks and informing precision medicine approaches.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-09529-3","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T15:02:37Z","timestamp":1758121357000},"page":"248-256","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["Learning the natural history of human disease with generative transformers"],"prefix":"10.1038","volume":"647","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2184-0856","authenticated-orcid":false,"given":"Artem","family":"Shmatko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8416-6849","authenticated-orcid":false,"given":"Alexander Wolfgang","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumar","family":"Gaurav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0316-5866","authenticated-orcid":false,"given":"S\u00f8ren","family":"Brunak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laust Hvas","family":"Mortensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8314-8497","authenticated-orcid":false,"given":"Ewan","family":"Birney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2370-8496","authenticated-orcid":false,"given":"Tom","family":"Fitzgerald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6709-963X","authenticated-orcid":false,"given":"Moritz","family":"Gerstung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"9529_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02317-2","volume":"9","author":"Z Zhu","year":"2018","unstructured":"Zhu, Z. et al. 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S.B. has ownership interests in Hoba Therapeutics Aps, Novo Nordisk, Lundbeck and Eli Lilly. E.B. is a consultant and shareholder of Oxford Nanopore. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}